CN106699760A - Method for synthesizing meropenem trihydrate - Google Patents
Method for synthesizing meropenem trihydrate Download PDFInfo
- Publication number
- CN106699760A CN106699760A CN201611253417.4A CN201611253417A CN106699760A CN 106699760 A CN106699760 A CN 106699760A CN 201611253417 A CN201611253417 A CN 201611253417A CN 106699760 A CN106699760 A CN 106699760A
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- China
- Prior art keywords
- meropenem
- synthetic method
- meropenem trihydrate
- raw material
- trihydrate
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- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 0 CC(CSC(C1)C=NC1*(N(C)C)=O)C(C1C(C)O)N(CCCO*O)C1=O Chemical compound CC(CSC(C1)C=NC1*(N(C)C)=O)C(C1C(C)O)N(CCCO*O)C1=O 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D477/00—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring
- C07D477/02—Preparation
- C07D477/06—Preparation from compounds already containing the ring or condensed ring systems, e.g. by dehydrogenation of the ring, by introduction, elimination or modification of substituents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D477/00—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring
- C07D477/10—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
- C07D477/12—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6
- C07D477/16—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6 with hetero atoms or carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 3
- C07D477/20—Sulfur atoms
Abstract
The invention relates to a method for synthesizing meropenem trihydrate and belongs to the technical field of synthesis of carbapenem antibiotics. The method for synthesizing meropenem trihydrate provided by the invention comprises the following steps: using protected meropenem (I) as a raw material, using a single solvent water as a reaction solvent, performing deprotection reaction with a non-hydrogen reducing agent in the presence of an alkali and a catalyst, and obtaining a target product meropenem trihydrate (II). The method provided by the invention is low in cost, not only solves the problem of dissolution of the catalyst by the reaction solvent, but also has advantages of less equipment investment, simple operation, mild reaction conditions, good selectivity, stable process, high yield and the like, and is suitable for industrial production.
Description
Technical field
The present invention relates to a kind of synthetic method of Meropenem trihydrate, belong to carbapenem antibiotics synthetic technology neck
Domain.
Background technology
Meropenem, also known as SM 7338, chemical name is 3- [5- [(dimethylamino) carbonyl] -3- pyrrolidinyls] sulphur
Generation] -6- (1- ethoxys) -4- methyl bicyclic [3,2, the 0] hept-2-ene" -2- carboxylic acids of -7- oxos miscellaneous nitrogen of -1-, structural formula is as follows：
Meropenem be SUMITOMO CHEMICAL Pharmaceutical Co., Ltd (Sumitomo Pharmaceuticals Co., Ltd) first
The second generation carbapenem antibiotic of exploitation, in Meropenem trihydrate form in January nineteen ninety-five with trade name Merrem
(U.S. is flat) listing.It is first carbapenem antibiotic of energy independent medication.Meropenem is due on the C-1 positions of structure
Introduce a methyl, this methyl to dehydropeptidase of kidney -1 (DHP-1) by resistance, thus, its without with DHP-1 inhibitor
Combination, can be with independent medication.Meropenem has the effect of the anti-Grain-positive of wide spectrum and negative bacterium, the medicine Central nervous system
And kidney is all very safe, enhance to gram negative bacilli, especially to the antibacterial activity of pseudomonas aeruginosa (PA).Its antibacterial
Spectrum almost includes clinically all of significant pathogenic bacteria, is the drug of first choice that treatment severe and multi-drug resistant bacteria infect at present
One of thing.
At present, it is that production Meropenem product must to nitrobenzyl, to nitro benzyloxy formoxyl that protection Meropenem (I) is de-
Through the step of one of, it is catalytic hydrogenation that the current step reacts usual way：In alkali in organic solvent or aqueous organic solvent
In the presence of, acted on by rhodium catalysis or palladium chtalyst and hydrogen reducing and sloughed to nitrobenzyl, to nitro benzyloxy formoxyl, so that
To Meropenem product (II).Catalytic hydrogenation must be carried out under high pressure, higher to equipment and operation requirement, and prepare reaction
Time is long, repeats yield low.
EP0126587A1 makes public for the first time Meropenem and preparation method thereof, is to protect Meropenem as raw material, with palladium
Carbon is catalyst, is entered in morpholinepropanesulfonic acid (MOPS) buffer solution (pH7.0) and tetrahydrofuran and ethanol solvent system
Row hydrogenation deprotection is obtained.Reaction is finished, reacting liquid filtering, organic solvent, washing is evaporated off, organic solvent is evaporated off again after through big
Macroporous adsorbent resin CHP-20P is purified, and obtains Meropenem.
The method the disadvantage is that, used MOPS to buffer still, and because reactant and product are dissolved in reaction solution,
Reaction speed is fast, and degradation product is more, also to go out to remove buffer and other impurity after reaction, it is necessary to carry out column chromatography for separation, behaviour
Make cumbersome, yield is low and purity difference.Using hydrogen reducing, equipment and operation are required high.
CN19950404A is action solvent, letter using water and the incompatible organic solvent of water on the basis of EP0126587A1
Changed processing step, but it is follow-up still need in the steps, and solution such as split-phase dissolved with part palladium complex, cause product heavy metal
It is exceeded.Still hydrogen reducing, plant issue is used to be still present.
CN1948312A is action solvent using water and water-miscible organic solvent on the basis of EP0126587A1, but is reacted
Thing and product are dissolved in reaction solution, and reaction speed is fast, and many problems of degradation product are still present.Equally applicable hydrogen reducing, equipment
Problem is still present.
CN102731504A uses water as single solvent on the basis of EP0126587A1, solves action solvent to urging
The problems of dissolution of agent, reduces product degraded, but still uses hydrogen reducing, plant issue still to allow presence.
CN102372715A has used non-hydrogen reducing agent, but still uses the buffering liquid for having N-methylmorpholine and acetic acid
System, and using organic solvents such as tetrahydrofurans, subsequent step still needs to split-phase, troublesome poeration.
Therefore, to solve problem present in prior art, it would be highly desirable to find with low cost a, process is simple, yield and
Purity is higher, and is adapted to the practicable synthetic route of large-scale production.
The content of the invention
It is an object of the invention to provide a kind of synthetic method of Meropenem trihydrate, its low cost is not only solved
Problems of dissolution of the action solvent to catalyst, and with low equipment investment, simple to operate, reaction condition be gentle, selectivity
Well, the advantages of process stabilizing, high income, it is adapted to industrialized production.
The synthetic method of Meropenem trihydrate of the present invention, it to protect Meropenem (I) is raw material to be, with list
One aqueous solvent is action solvent, under conditions of alkali and catalyst are present, deprotection reaction is carried out using non-hydrogen reducing agent, is obtained
Target product Meropenem trihydrate (II)；
The structural formula of protection Meropenem (I) and Meropenem trihydrate (II) is as follows respectively：
The consumption of the single solvent water is 10~30 times of raw material protection Meropenem weight.
The alkali is sodium iso-octoate or sodium acetate, and the consumption of alkali is 3~5 times of raw material protection Meropenem molar equivalent.
The catalyst is the palladium carbon of mass percent concentration 5%~10%, and catalyst is that raw material protects Meropenem weight
The 10%~30% of amount.
The non-hydrogen reducing agent is the aqueous solution of formaldehyde；Non-hydrogen reducing agent consumption is raw material protection Meropenem weight
15%-30%.
The mass fraction of the formaldehyde in aqueous solution of the formaldehyde is 35-45%.
The reaction temperature is 2~8 DEG C, and the reaction time is 2~5 hours.
The present invention compared with prior art, has the advantages that：
For causing cumbersome, yield low and purity difference using double solvent in the prior art, must using catalytic hydrogenation
Must carry out under high pressure, higher to equipment and operation requirement, the reaction time is long, the low problem of yield, and the present invention is using single
Solvent-water solves problems of dissolution of the action solvent to catalyst, or solve as action solvent, low cost, environmental protection
Using buffer system or the post processing problem of organic solvent, product degradation rate is reduced, improve product purity；The present invention is adopted
Non-hydrogen reducing agent is used, can be carried out at ambient pressure, with low cost, low equipment investment, simple to operate, reaction condition be gentle, selection
Property good, process stabilizing, high income the advantages of, be adapted to industrialized production, the molar yield of target product is up to more than 85%, purity
Up to more than 99.50%.
Specific embodiment
With reference to embodiment, the present invention is further illustrated, but it is not intended to limit implementation of the invention.
Embodiment 1
Purified water 200ml, protection Meropenem 20g, sodium iso-octoate 23.80g, 10% palladium carbon are added in reaction bulb
3g, 35% formalin 6g, 7 DEG C of temperature control react 2.5 hours, filtering, and 5 DEG C~10 DEG C of temperature control in filtrate to being added dropwise acetone
400ml, is cooled to 0 DEG C, and growing the grain 1h, suction filtration, filter cake 100ml acetone drip washing is drained, and is vacuum dried at 30 DEG C~40 DEG C and obtained final product
Meropenem trihydrate crude product 10.68g, molar yield 85.20%, HPLC purity 99.60%.
Embodiment 2
Purified water 600ml, protection Meropenem 20g, sodium iso-octoate 14.35g, 5% palladium carbon 2g are added in reaction bulb,
40% formalin 4.5g, 3 DEG C of temperature control reacts 5 hours, filtering, 5 DEG C~10 DEG C of temperature control to acetone 400ml is added dropwise in filtrate,
0 DEG C is cooled to, growing the grain 1h, suction filtration, filter cake 100ml acetone drip washing is drained, vacuum drying obtains final product Metro training at 30 DEG C~40 DEG C
Southern trihydrate crude product 10.69g, molar yield 85.30%, HPLC purity 99.50%.
Embodiment 3
Purified water 400ml, protection Meropenem 20g, sodium acetate 15.60g, 8% palladium carbon 6g are added in reaction bulb,
45% formalin 3g, 5 DEG C of temperature control reacts 3 hours, filtering, and 5 DEG C~10 DEG C of temperature control drops to acetone 400ml is added dropwise in filtrate
Temperature to 0 DEG C, drain by growing the grain 1h, suction filtration, filter cake 100ml acetone drip washing, and vacuum drying obtains final product Meropenem at 30 DEG C~40 DEG C
Trihydrate crude product 10.67g, molar yield 85.10%, HPLC purity 99.80%.
Comparative example 1
Tetrahydrofuran 350ml is added in reaction bulb, protects Meropenem 20g, 10% palladium carbon 3g, 5 DEG C of temperature control to be passed through
Hydrogen reacts 6 hours to pressure in the bottle 1.5MPa is reacted, filtering, and 5 DEG C~10 DEG C of temperature control is to dropwise addition acetone 400ml in filtrate, drop
Temperature to 0 DEG C, drain by growing the grain 1h, suction filtration, filter cake 100ml acetone drip washing, and vacuum drying obtains final product Meropenem at 30 DEG C~40 DEG C
Trihydrate crude product 8.80g, molar yield 70.20%, HPLC purity 97.58%.
Claims (7)
1. a kind of synthetic method of Meropenem trihydrate, it is characterised in that：It is raw material to protect Meropenem (I), with list
One aqueous solvent is action solvent, under conditions of alkali and catalyst are present, deprotection reaction is carried out using non-hydrogen reducing agent, is obtained
Target product Meropenem trihydrate (II)；
The structural formula of protection Meropenem (I) and Meropenem trihydrate (II) is as follows respectively：
2. the synthetic method of Meropenem trihydrate according to claim 1, it is characterised in that：The use of single solvent water
Measure is 10~30 times of raw material protection Meropenem weight.
3. the synthetic method of Meropenem trihydrate according to claim 1, it is characterised in that：Alkali be sodium iso-octoate or
Sodium acetate, the consumption of alkali is 3~5 times of raw material protection Meropenem molar equivalent.
4. the synthetic method of Meropenem trihydrate according to claim 1, it is characterised in that：Catalyst is quality hundred
Divide the palladium carbon of specific concentration 5%~10%, catalyst is the 10%~30% of raw material protection Meropenem weight.
5. the synthetic method of Meropenem trihydrate according to claim 1, it is characterised in that：Non-hydrogen reducing agent is first
The aqueous solution of aldehyde；Non-hydrogen reducing agent consumption is the 15%-30% that raw material protects Meropenem weight.
6. the synthetic method of Meropenem trihydrate according to claim 5, it is characterised in that：In the aqueous solution of formaldehyde
The mass fraction of formaldehyde is 35-45%.
7. the synthetic method of Meropenem trihydrate according to claim 1, it is characterised in that：Reaction temperature is 2~8
DEG C, the reaction time is 2~5 hours.
Priority Applications (1)
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| CN201611253417.4A CN106699760B (en) | 2016-12-30 | 2016-12-30 | The synthetic method of Meropenem trihydrate |
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| CN201611253417.4A CN106699760B (en) | 2016-12-30 | 2016-12-30 | The synthetic method of Meropenem trihydrate |
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| CN106699760A true CN106699760A (en) | 2017-05-24 |
| CN106699760B CN106699760B (en) | 2019-01-18 |
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102133527A (en) * | 2010-12-23 | 2011-07-27 | 西安凯立化工有限公司 | Palladium tin carbon catalyst for meropenem synthesis and preparation method |
| CN102336756A (en) * | 2010-07-20 | 2012-02-01 | 湖北益泰药业有限公司 | Deprotection method in meropenem synthesis |
| CN102348710A (en) * | 2009-03-13 | 2012-02-08 | 株式会社大熊制药 | Improved method for preparing meropenem using zinc powder |
| CN102372715A (en) * | 2011-12-07 | 2012-03-14 | 凯莱英医药集团（天津）股份有限公司 | Method for preparing meropenem |
| CN102731504A (en) * | 2011-04-13 | 2012-10-17 | 石药集团中奇制药技术（石家庄）有限公司 | Preparation method of meropenem |
| CN103894190A (en) * | 2014-04-29 | 2014-07-02 | 西安凯立化工有限公司 | Preparation method of palladium-carbon catalyst for synthesizing meropenem |
-
2016
- 2016-12-30 CN CN201611253417.4A patent/CN106699760B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102348710A (en) * | 2009-03-13 | 2012-02-08 | 株式会社大熊制药 | Improved method for preparing meropenem using zinc powder |
| CN102336756A (en) * | 2010-07-20 | 2012-02-01 | 湖北益泰药业有限公司 | Deprotection method in meropenem synthesis |
| CN102133527A (en) * | 2010-12-23 | 2011-07-27 | 西安凯立化工有限公司 | Palladium tin carbon catalyst for meropenem synthesis and preparation method |
| CN102731504A (en) * | 2011-04-13 | 2012-10-17 | 石药集团中奇制药技术（石家庄）有限公司 | Preparation method of meropenem |
| CN102372715A (en) * | 2011-12-07 | 2012-03-14 | 凯莱英医药集团（天津）股份有限公司 | Method for preparing meropenem |
| CN103894190A (en) * | 2014-04-29 | 2014-07-02 | 西安凯立化工有限公司 | Preparation method of palladium-carbon catalyst for synthesizing meropenem |
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Effective date of registration: 20200803 Address after: 256100 Yiyuan Economic Development Zone, Shandong, Zibo Patentee after: SHANDONG XINQUAN PHARMACEUTICAL Co.,Ltd. Address before: 256100 Yiyuan Economic Development Zone, Shandong, Zibo Patentee before: ZIBO XINQUAN PHARMACEUTICAL TECHNOLOGY SERVICE Co.,Ltd. |
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Denomination of invention: Synthesis of meropenem trihydrate Effective date of registration: 20211216 Granted publication date: 20190118 Pledgee: Commercial Bank of China Yiyuan branch of Limited by Share Ltd. Pledgor: SHANDONG XINQUAN PHARMACEUTICAL Co.,Ltd. Registration number: Y2021980015204 |
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Date of cancellation: 20220721 Granted publication date: 20190118 Pledgee: Commercial Bank of China Yiyuan branch of Limited by Share Ltd. Pledgor: SHANDONG XINQUAN PHARMACEUTICAL Co.,Ltd. Registration number: Y2021980015204 |